Transvenous phrenic nerve stimulation to treat idiopathic central sleep apnea

Abstract

Study objectives: Idiopathic central sleep apnea (ICSA) is a rare disorder diagnosed when known causes of central sleep apnea are excluded. No established treatments exist for ICSA, and long-term studies are lacking. We assessed the long-term effectiveness and safety of transvenous phrenic nerve stimulation in patients with ICSA.

Methods: In the remedē System Pivotal Trial, 16/151 (11%) participants with central sleep apnea were diagnosed as having ICSA. Patients were implanted and followed through 18 months of active therapy. Polysomnograms obtained at baseline and at 6, 12, and 18 months were scored by a central laboratory. Sleep metrics and patient-reported quality of life outcomes were assessed.

Results: Patients experienced moderate-severe central sleep apnea. The baseline AHI, central apnea index, and arousal index were 40, 25, and 32 events/h of sleep, respectively. These metrics improved at 6, 12, and 18 months of therapy: the AHI decreased by 25, 25, and 23 events/h (P < .001 at each visit), the central apnea index by 22, 23, and 22 events/h (P < .001 at each visit), and the arousal index by 12 (P = .005), 11 (P = .035), and 13 events/h (P < .001). Quality of life instruments showed clinically meaningful improvements in daytime somnolence, fatigue, general and mental health, and social functioning. The only related serious adverse event was lead component failure in 1 patient.

Conclusions: This is the longest prospective study for the treatment of ICSA. Transvenous phrenic nerve stimulation significantly decreased sleep-disordered breathing metrics with consequent improvement in quality of life at 6 months, and all benefits were sustained through 18 months.

Clinical trial registration: Registry: ClinicalTrials.gov; Name: Respicardia, Inc. Pivotal Trial of the remedē System; URL: https://clinicaltrials.gov/ct2/show/NCT01816776; Identifier: NCT01816776.

Keywords: idiopathic central sleep apnea; quality of life; transvenous phrenic nerve stimulation.

Figure 1. Phrenic nerve stimulation on/off in ICSA.

Example of a 5-minute segment of sleep from a polysomnogram showing epochs of sleep for a patient with ICSA. The left side (Therapy Off) shows the pattern of sleep with central apnea events before initiation of therapy; the pattern looks very different than the Cheyne-Stokes respiration pattern associated with CSA in patients with heart failure. The right side (Therapy On) shows the immediate cessation of central apneas and the resumption of normal sleep when TPNS therapy is turned on. CSA = central sleep apnea, ICSA = idiopathic central sleep apnea, TPNS, transvenous phrenic nerve stimulation.

Figure 2. Polysomnogram sleep metrics by visit.

Sleep indices from overnight, attended PSG for the subgroup of patients with ICSA. Indices with Wilcoxon signed rank test nominal 2-sided P value < .05 for change from baseline at each follow-up visit are identified with *. ArI = arousal index, CAI = central apnea index, HI = hypopnea index, ICSA = idiopathic central sleep apnea, MAI = mixed apnea index, OAI = obstructive apnea index, ODI4 = oxygen desaturation index (4%), PSG = polysomnography.

Figure 3. QoL.

QoL improved with phrenic nerve stimulation. The ESS and FSS are used at the left (black) y axis; the EQ-5D is used at the right (red) y axis. The median ESS improved from > 10 points, which indicates excessive daytime sleepiness, to < 10 points at each visit with TPNS therapy. The median FSS improved from > 4 points, which indicates fatigue, to < 4 points at each visit with TPNS therapy. The median EQ-5D showed minimal change after 6 months of therapy, but a statistically significant improvement (to the best health state) was observed at 12 months. ESS = Epworth Sleepiness Scale, FSS = Fatigue Severity Scale, QoL = quality of life, TPNS = transvenous phrenic nerve stimulation.

Figure 4. SF-12 component and domain scores.

The SF-12 mental component, physical component, and 8 domain scores are displayed by visit; a score of 50 is considered the U.S. population norm. Statistically significant improvements were observed for general health at 12 months and for mental health at 6 months. None of the scores showed a significant worsening with therapy. SF-12 = 12-item short-form survey.